P512: A PHASE 1B/2 STUDY OF TP-0903 AND DECITABINE TARGETING MUTANT TP53 AND/OR COMPLEX KARYOTYPE IN PATIENTS WITH UNTREATED ACUTE MYELOID LEUKEMIA (AML) ≥ AGE 60 YEARS: FINAL RESULTS
Authors: Alice Mims, Ying Huang, Eric Eisenmann, Shelley Orwick, Daelynn Buelow, Ronan Swords, Joshua Zeidner, Matthew Foster, Tara L. Lin, Maria Baer, Yazan Madanat, Tibor Kovacsovics, Robert Redner, Zeina Al-Mansour, Mona Stefanos, Molly Martycz, Franchesca Druggan, Timothy Chen, Ashley Yocum, Uma Borate, Brian Druker, Amy Burd, Ross Levine, Sharyn Baker, John C. Byrd
Journal: HemaSphere (2023)

Background: TP-0903 is a multi-kinase inhibitor designed to target AXL, but also inhibits additional kinases relevant to the progression of AML, including those regulating the cell cycle, such as Chk1/2. Pre-clinical studies of TP-0903 and decitabine (dec) showed additive cytotoxicity in vitro and prolonged survival in mouse models of TP53-mutant (TP53m) AML, a poor prognostic sub-group of AML. Here we report the clinical and safety results from the Leukemia and Lymphoma Society’s BeatAML phase 1b/2 (Ph1b/2) trial of TP-0903 in combination with dec (ClinicalTrials.gov NCT03013998). Aims: To establish the recommended dose of TP-0903 combined with dec and evaluate its efficacy in newly diagnosed older AML patients with TP53 mutations and/or complex karyotype (CK). Methods: Newly diagnosed AML patients ≥60 years with TP53m and/or CK (defined as ≥3 abnormalities) were consented, screened and assigned to this Ph1b/2 study by the BeatAML Master Trial. A standard 3 + 3 design was used for Ph1b to determine the initial recommended dose of TP-0903 (Days 1-21, 37 mg/day) in combination with dec (Days 1-10, 20 mg/m2) in a 28-day cycle. Ph2 followed a Simon’s 2-stage design in which, to move onto the 2nd stage, the 1st stage required 4 or more CR responses by the end of induction therapy (up to 3 cycles) or CRh/CRi/MLFS induction responses that converted to CR by 6 cycles. Nine additional patients were treated at 37 mg during Ph2, in which further assessments of safety, pharmacokinetic (PK) and pharmacodynamic data were used to amend the protocol and update the final recommended Ph2 dose of TP-0903 to 25 mg/day. Results: Of 27 total patients who started therapy with TP-0903, 15 received 37 mg and 12 received 25 mg. Two patients treated with 37 mg achieved CR and 3 achieved CRh, for a complete response (CR/CRh/CRi) rate of 33.3% (95% CI, 11.8 – 61.6). Three patients treated with 25 mg achieved CR, 1 achieved CRh, and 2 achieved CRi, for a complete response rate of 50% (95% CI, 21.1 – 78.9). Additionally, 4 patients treated with 37 mg were minimal residual disease (MRD) negative, measured by flow cytometry after 3 or 6 cycles of therapy, while only 2 patients treated with 25 mg obtained MRD- status. The median response duration for patients who achieved a complete response was 13.8 months (95%CI, 7.3 – Not Estimable (NE); median Follow-Up (FU), 16.7, 16.7 months) for those treated with 37 mg and 4.6 months (95%CI, 1.8 – NE; median FU, 4.4 months) for those treated with 25 mg. The median overall survival was 7.6 months (95%CI, 2.0 – 20.6; median FU, 17.1 months) for all patients treated at 37 mg and 7.5 months (95%CI, 1.1 – NE; median FU, 7.6 months) for those treated at 25 mg. Grade 3+ treatment-related adverse events were similar in patients treated with 37 mg and 25 mg TP-0903. The most common events in patients treated with 37 mg were neutropenia (33.3%), thrombocytopenia (26.7%), leukopenia (20%), and anemia (13.3%). Likewise, the most common events in patients treated with 25mg were neutropenia (50%), decreased lymphocyte counts (41.7%), febrile neutropenia (33.3%), leukopenia (33.3%), and thrombocytopenia (25%). Summary/Conclusion: Although the 1st stage in the Ph2 portion of the trial was terminated early after treating only 11 patients with 25 mg TP-0903 + dec, the trial still achieved 3 of the 4 required CR responses needed to move onto the 2nd stage. Additionally, 3 other patients in this group achieved responses of CRh (1) and CRi (2). This combination regimen is encouraging, considering the high risk and poor outcome of patients with TP53m and/or CK AML.Keywords: Phase I/II, Acute myeloid leukemia, Tyrosine kinase inhibitor